Our goal is to determine the mechanism of abnormal brain function in severe liver disease. Particular attention will be devoted toward establishing unequivocably whether ammonia is a primary toxin to the central nervous system and whether a direct relationship exists between abnormal cerebral ammonia metabolism and hepatic encephalopathy. Toward these ends, we have several approaches: 1) To examine the uptake and metabolism of 13NH3 entering brain in normal individuals and patients with liver disease; 2) To determine the metabolic fate and rate of turnover of 13NH3 in brains of normal rats and of rats made chronically hyperammonemic by a portacaval shunt; 3) To assess the 24-hour blood ammonia levels in normal subjects and patients with liver disease, and to determine the relationships between brain, blood, and cerebrospinal fluid ammonia concentrations in normal and protacaval animals; and 4) To evaluate the effect of ammonia intoxication on intracellular transport of reducing equivalents via the malate-aspartate shuttle system. The findings should provide new insights into the degree to which cerebral ammonia metabolism is altered in conditions of chronic hyperammonemia in man; they may also offer clues as to the biochemical mechanisms of ammonia intoxication. Because hyperammonemia is generally believed to be a major pathogenetic factor in human hepatic encephalopathy, a clarification of the role of abnormal ammonia metabolism in patients with this condition may suggest more effective lines of therapy.